Most complex trait-associated variants are located in non-coding regulatory regions of the genome, where they have been shown to disrupt transcription factor (TF)-DNA binding motifs. Variable TF-DNA interactions are therefore increasingly considered as key drivers of phenotypic variation. However, recent genome-wide studies revealed that the majority of variable TF-DNA binding events are not driven by sequence alterations in the motif of the studied TF. This observation implies that the molecular mechanisms underlying TF-DNA binding variation and, by extrapolation, inter-individual phenotypic variation are more complex than originally anticipated. Here, we summarize the findings that led to this important paradigm shift and review proposed mechanisms for local, proximal, or distal genetic variation-driven variable TF-DNA binding. In addition, we discuss the biomedical implications of these findings for our ability to dissect the molecular role(s) of non-coding genetic variants in complex traits, including disease susceptibility.
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